The technical field of the invention concerns methods and compositions for the treatment of neurodegenerative diseases by proteasome modulators.
The proteasome (also known as macropain, the multicatalytic protease, and 20S protease) is a high molecular weight, multisubunit protease which has been identified in every examined species from an archaebacterium to human. The enzyme has a native molecular weight of approximately 650,000 and, as revealed by electron microscopy, a distinctive cylinder-shaped morphology (Rivett, (1989) Arch. Biochem. Biophys. 268:1-8; and Orlowski, (1990) Biochemistry 29:10289-10297). The proteasome subunits range in molecular weight from 20,000 to 35,000 (3-5), and are homologous to one another but not to any other known protease.
The proteasome enzyme is “multicatalytic,” i.e. it has at least three distinctly different catalytic sites including: a peptidylglutamyl-peptide hydrolyzing site, which cleaves peptides with glutamic acid in the P1 position (e.g. CBZ-Leu-Leu-Glu-X); a “trypsin-like” site, which cleaves peptides with basic amino acids in the P1 position (e.g. CBZ-Val-Leu-Arg-X); and a “chymotrypsin-like” site, which cleaves peptides with leucine or other hydrophobic amino acids in the P1 position (e.g. CBZ-Gly-Gly-Leu-X). The proteasome has been identified in both cytoplasmic and nuclear compartments and appears to play a central role in non-lysosomal pathways of intracellular protein degradation, including those mediated by ATP and ubiquitin (McGuire, et al. (1988) Arch. Biochem. Biophys. 262:272-285; McGuire, et al. (1989) Biochim. Biophys. Acta 967:195-203; McGuire, et al. (1989) Biochem. Biophys. Res. Commun. 160:911-916; DeMartino, et al. (1991) Biochim. Biophys. Acta 1073:299-308; and Hershko, et al. (1992) Ann. Rev. Biochem. 61:761-807). Its activity is high in muscle wasting diseases that involve protein breakdown such as muscular dystrophy, cancer and AIDS. Evidence also suggests a possible role for the proteasome in the processing of antigens for the class I MHC molecules (Goldberg, et al. (1992) Nature 357:375-379).
Proteasomes may be involved in neurodegenerative diseases and disorders such as Amyotrophic Lateral Sclerosis (ALS). Neurodegenerative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual. In addition to ALS, various other diseases, such as Huntington's disease, Parkinson's disease, Alzheimer's disease and Multiple Sclerosis, fall within this category. These diseases are debilitating and the damage that they cause is often irreversible. Moreover, in the case of a number of these diseases, the outcome is invariably fatal.
Progress is being made on many fronts to find agents that can arrest the progress of these diseases. Nonetheless, the present therapies for most, if not all, of these diseases provide very little relief.
Accordingly, a need exists to develop therapies that can alter the course of neurodegenerative diseases or, in the case of diseases like ALS, prolong the survival time of patients with such diseases. More generally, a need exists for better methods and compositions for the treatment of neurodegenerative diseases in order to improve the quality of the lives of those afflicted by such diseases.